Structural biologists are deciphering the mechanisms of biological macromolecules at a breathtaking pace. X-ray crystallography has provided atomic resolution structures of complex molecular assemblies, such as the ribosome and RNA polymerase, of sizes that would have been unimaginable just a short time ago. NMR spectroscopy is allowing us to probe not just the structure, but also the dynamics, of ever larger molecules of proteins and nucleic acids in solution and in membranes. This wealth of structural information is complemented by dramatic improvements in the computational analysis of the structure and dynamics of biological macromolecules. The integration of all this new information requires an inter-disciplinary approach that utilizes a wide range of biochemical and biophysical tools to probe molecular function, while keeping the biologically important questions at center stage. The proposed Keystone Meeting will bring together structural biologists interested in these issues, which have deep implications both for fundamental biology and for the process of drug discovery.